Anti-arthritic compositions comprising phosphine or phosphite gold complexes of thiobenzoic acid and substituted thiophenols and methods of producing anti-arthritic activity

ABSTRACT

Phosphine or phosphite gold complexes of thiobenzoic acid and substituted thiophenols having anti-arthritic activity are prepared by reaction of an appropriate phosphine or phosphite gold(I) halide with a substituted thiobenzoic acid or a substituted thiophenol in the presence of alkali.

-United States Patent [1 1 Sutton et al.

1 ANTI-ARTHRITIC COMPOSITIONS COMPRISING PIIOSII'IINE OR PHOSPHITE GOLDCOMPLEXES OF TI-IIOBENZOIC ACID AND SUBSTITUTED TI'IIOPI'IENOLS ANDMETHODS OF PRODUCING ANTI-ARTHRITIC ACTIVITY [75] Inventors: Blaine M.Sutton, Hatboro; Joseph Weinstock, Phoeni iville, both of Pa.

[73] Assignee: SmlthKline Corporation,

I Philadelphia, Pa.

[22] Filed: July 17, 1974 [211 Appl. No.: 489,197

Related U.S. Application Data 62] Division of Ser. No. 381,832. July 23.I973, Pat. No. 3,842,107.

[4 1 Sept. 2, 1975 [52] U.S. Cl. 424/223 [5 l Int. Cl. [58] Field ofSearch 424/223 Primary Examiner-Stanley .l. Friedman Attorney, Agent, orFirm-Janice E. Williams; Richard D. Foggio; William H. Edgerton [57]ABSTRACT 15 Claims, No Drawings ANTI-ARTHRITIC COMPOSITIONS COMPRISINGPHOSPHINE OR PI-IOSPHITE GOLD COMPLEXES OF THIOBENZ OIC ACID ANDSUBSTITUTED Tl-IIOPHENOLS AND METHODS OF PRODUCING ANTI-ARTHRITICACTIVITY This is a division of application Ser. No. 381,832 filed July23, 1973 now US. Pat. No. 3,842,107.

This invention relates to novel phosphine or phosphite gold complexes ofthiobenzoic acid and substituted thiophenols which have usefulpharmacological activity. More specifically, the compounds of this invention have anti-arthritic activity as measured by their ability toinhibit adjuvant-induced polyarthritis in rats.

The compounds of this invention are represented by the followingstructural formula:

FORMULA I in which:

, R is lower alkyl, lower alkoxy, phenyl or phenoxy with each alkyl oralkoxy having from one to three carbon atoms;

Y is a carbon-sulfur single bond or C=O;

R is hydrogen, amino or COOM when Y is C=O, or amino or COOM when Y is acarbonsulfur single bond; and

M is hydrogen or an alkali metal cation.

Preferred compounds of this invention are representedby Formula I whereR is lower alkyl of from one to three carbon atoms. Also preferred arethose compounds of Formula I where R is hydrogen when Y is C=O.

The compounds of this invention are prepared by reaction of asubstituted thiobenzoic acid or a substituted thiophenol with aphosphine or phosphite gold halide, for example triethylphosphinegold(l)chloride, in the presence of alkali such as sodium or potassiumhydroxide in a solvent such as ethanol or aqueous ethanol at about 25for one hour. When R is carboxy, the reaction mixture is acidified toliberate the free acid product. The product phosphine or phosphite goldcomplexes are purified by standard crystallization or chromatographictechniques.

The phosphine or phosphite gold halides employed as starting materialsare prepared by reaction of a cold (-l to 5) solution of gold(I)chloride, prepared by mixing thiodiglycol and gold acid chloridetrihydrate in aqueous alcohol, with an appropriate phosphine orphosphite. Other procedures which may be applied to the preparation ofthese intermediates are found in J. Chem. $06., 1828 (1937) and 1235(i940) and Australian J. Chem., 19:547 (1966).

Some phosphine and phosphite gold complexes are known to haveanti-arthritic activity, but their utility is limited by the requirementthat they be administered by the parenteral route. The compounds of thisinvention have the distinct advantage of being active upon oraladministration.

Although the preparation of S-triethylphosphine(thiophenyl)gold isdescribed [Australian J. Chem 19:539 l966 )1, the benzoyl derivativesand substituted phenyl derivatives are not reported. No pharmacologicalactivity has been disclosed for compounds of this class.

The anti-arthritic activity of the compounds of this invention ismeasured by their ability to inhibit adjuvant-induced polyarthritis inrats. The compounds of Formula l produce marked inhibition of thedevelop ment of adjuvant arthritis in rats at daily oral doses as low asabout 10 mg. per kilogram of body weight. Of particular importance isthe attainment of significant serum levels of gold following oraladministration of these doses. v

Adjuvant arthritisin rats is produced by a' single injection of 0.75 mg.of Mycobacterium butyricum suspended in white paraffin (N.F.) into ahindpaw (left footpad). The injected leg becomes inflamed and reaches amaximum volume in three to five days (primary lesion). Theanimals'exhibit a decrease in body weight gain during this initialperiod. Adjuvant arthritis (secondary phase) occurs after a delay ofapproximately ten days and is characterized by inflammation of thenon-injected sites (right hind leg), decrease in body weight gain andfurther increases in the volume of the injected hind leg. The compoundsof Formula I administered in the doses described above beginning on theday of adjuvant injection and continuing for 17 days thereafter,exclusive of days 4, 5 l l and 12, protect the animals againstdevelopment of both primary and secondary lesions of adjuvant arthritis.

The compounds of this invention are administered in conventional dosageunit forms by incorporating an amount sufficient to produceanti-arthritic activity, without toxic effects, with a nontoxicpharmaceutical carrier according to accepted procedures. Preferably thedosage units will contain a phosphine gold complex of Formula I or analkali metal salt thereof where R is carboxy in an amount of from about0.5 mg. to about 5 mg, calculated on gold content, per unit.

The pharmaceutical carrier employed may be, for example, either a solidor liquid. Exemplary of solid carriers are lactose, terra alba, sucrose,talc, gelatin, agar, pextin, pectin, magnesium stearate, stearic acidand the like. Exemplary of liquid carriers are syrup, peanut oil, oliveoil, water and the like. Similarly, the carrier or diluent can includeany time delay material well known to the art, such as glycerylmonostearate or glyceryl distearate alone or with a wax.

A wide variety of pharmaceutical forms can be employed. Thus, if a solidcarrier is used the preparation can be tableted, placed in a hardgelatin capsule in powder or pellet form or in the form of a troche or102- enge. The amount of solid carrier will vary widely but preferablywill be from about 25 mg. to about 1 g. If a liquid carrier is used, thepreparation will be in the form of a syrup, emulsion, soft gelatincapsule, sterile injectable liquid such as an ampule or an aqueous ornonaqueous liquid suspension.

The pharmaceutical dosage unit forms described hereinabove excludesimple non-sterile solutions of the active medicament in water or incommon organic solvents and exclude simple aqueous suspensions of theactive medicament in the absence of a suspending agent.

The method of producing anti-arthritic activity in accordance with thisinvention comprises administering internally to an animal organism aphosphine gold complex of Formula I, usually combined with apharmaceutical carrier, in an amount sufficient to produce antiarthriticactivity without limiting side effects. The active medicament will beadministered in a dosage unit, as described above, orally orparenterally the oral route being preferred. Advantageously equal doseswill be administered one or two times daily with the daily dosageregimen being from about 0.5 mg. to about mg., calculated on goldcontent. When the method described above is carried out, anti-arthriticactivity is produced with a minimum of side effects.

The pharmaceutical preparations are made following the conventionaltechniques of the pharmaceutical chemist involving mixing, granulatingand compressing when necessary, or variously mixing and dissolving theingredients as appropriate to the desired end product.

The following examples illustrate the preparation of compounds of thisinvention and their incorporation into pharmaceutical compositions, andas such are not to be considered as limiting the invention set forth inthe claims appended hereto. Temperatures are in degrees Centigradeunless otherwise stated.

EXAMPLE 1 S-Triethylphosphine(thiobenzoyl gold A solution of 10.0 g.(0.08 mol.) of thiodiglycol in 25 ml. of ethanol was mixed with asolution of 15.76 g. (0.04 mol.) of gold acid chloride trihydrate in 75ml. of distilled water. When the bright orange-yellow solution wasalmost colorless, it was cooled to below 5 and an equally cold solutionof 5.0 g. (0.0425 mol.) of triethylphosphine in 25 ml. of ethanol wasadded dropwise to the stirred solution. After addition, the cooledmixture was stirred for 30 minutes. The solid that separates was removedby filtration and the filtrate was concentrated to about 30 ml. to yielda second crystal crop. The combined solid was washed with aqueousethanol (2:1) and recrystallized from ethanol by addition of water tothe cloud point to give triethylphosphinegold( I) chloride as whiteneedles, m.p. 8586.

To a solution of 0.69 g. (0.005 mol.) of thiobenzoic acid in ml. ofethanol was added 0.28 g. (0.005 mol.) of potassium hydroxide in 10 ml.of ethanol followed by 1.75 g. (0.005 mol.) of triethylphosphinegold(l)chloride in 25 ml. of ethanol. The reaction mixture was stirred foronehour at 25 under nitrogen, then it was filtered and the filtrate wasevaporated to dryness. The residue was taken up in about ml. ofchloroform and chromatographed on 50 g. of silica gel with benzene andbenzene-methanol (1:1) to give the title compound, m.p. 6870 (methanol).

EXAMPLE 2 S-Triethylphosphine( 2-carboxyphenylthio gold To a solution of0.400 g. (0.01 mol.) of sodium hydroxide in 20 ml. of aqueous ethanol(1:1) was added 0.77 g. (0.005 mol.) of o-mercaptobenzoic acid in 20 ml.of ethanol, followed by 1.75 g. (0.005 mol.) of triethylphosphinegold(l)chloride in 20 ml. of ethanolchloroform l :1 The solution was stirred atunder nitrogen for one hour, then it was filtered and the filtrate wasacidified with 6 ml. of 1N acetic acid to about pH 5.5. The acidicsolution was evaporated to dryness and the residue was dissolved inchloroform. The chloroform solution was dried (MgSO and concentrated togive the title compound, m.p. 109.51 10.

EXAMPLE 3 S-Triethylphosphine(2-aminophenylthio gold To a cold solutionof 2.52 g. (0.02mol.) of 2- aminothiophenol in 20 ml. of ethanol wasadded 0.80 g. (0.02 mol.) of sodium hydroxide in 10 ml. of waterfollowed by 7.0 g. (0.02 mol.) of triethylphosphinegold(l) chloride in40 ml. of ethanol. A white precipitate formed immediately. The reactionmixture was stirred at 25 under nitrogen for one hour, then theprecipitate was collected by filtration to give the title compound, m.p.8788.5 (methanol).

EXAMPLE 4 S-Triisopropylphosphine(thiobenzoyl) gold A solution of 11.82g. (0.03 mol.) of gold acid chloride trihydrate and 7.9 g. (0.065 mol.)of thiodiglycol in ml. of aqueous ethanol (3:2) was stirred until thecolor of auric gold disappeared. The almost colorless solution wascooled below 5 and an equally cold solution of 5.6 g. (0.035 mol.) oftriisopropylphosphine in 20 ml. of ethanol was added dropwise. Thevolume of the final reaction mixture was increased to 250 ml. with 1:1aqueous ethanol in order to maintain a fluid mixture. After addition,the mixture was stirred in the cold for 45 minutes. The solid wasremoved by filtration, washed with 1:2 alcohol-water, then dried. It wasredissolved by suspension in ethanol and addition of sufficientmethylene chloride for solution. The cloudy solution was filtered fromsuspended gold and the filtrate was concentrated until crystallizationto give triisopropylphosphinegold(I) chloride as white crystals, m.p.1841 86.

When an equivalent amount of triisopropylphosphinegold(l) chloride issubstituted in the procedure of Example 1 for triethylphosphinegold(l)chloride, the title compound is obtained.

EXAMPLE 5 When an equivalent amount of triisopropylphosphinegold(l)chloride is substituted in the procedure of Example 2 fortriethylphosphinegold(l) chloride, S-

triisopropylphosphine( 2-carboxyphenylthio gold is ob- EXAMPLE 6S-Trimethylphosphine(thiobenzoyl) gold A solution of 2.44 g. (0.02 mol.)of thiodiglycol in 15 ml. of methanol was mixed with a solution of 3.98g. (0.01 mol.) of gold acid chloride trihydrate in 25 ml. of distilledwater. When the orange-yellow solution became almost colorless, it wascooled to 15 and an equally cold solution of 760 mg. (0.01 mol.) oftrimethylphosphine in 10 ml. of methanol was added dropwise to thestirred solution. After theaddition, the cooled mixture was stirred for30 minutes. The product was filtered off and the filtrate wasconcentrated in vacuo to give a second crystal crop. The combinedproduct was washed with cold aqueous methanol (2:1) and water to givetrimethylphosphinegoldfl) chloride, m.p. 228229.

When an equivalent amount of trimethylphosphinegold(l) chloride issubstituted in the procedure of Example 1 for triethylphosphinegoldfl)chloride, the title compound is obtained.

EXAMPLE 7 EXAMPLE 8 d i .S-Triphenylphosphine(thiobenzoyl)gold Gold acidchloride trihydrate (4.0 g; 0.01 mol.) was reduced to aurous chloridewith thiodiglycol in 1:2 aqueous ethanol. After cooling this solution inan ice bath, a cold solution of 2.62 g. (0.01 mol.) oftriphenylphosphine in a minimum amount of ethanol was added with stirring. The reaction mixture was stirred for about 30 minutes, then it wasfiltered and the product was washed with cold aqueous alcohol and waterand dried to give triphenylphosphinegold(l) chloride, m.p. 242 243".

Substitution of an equivalent amount of triphenyL phosphinegold(l)chloride in the procedure of Example l for triethylphosphinegoldfl)chloride gives the title compound.

EXAMPLE 9 When an equivalent amount of triphenylphosphinegold(l)chloride is substituted in the procedure of Example 2 fortriethylphosphinegold(l) chloride, S-triphenylphosphine(2-carboxyphenylthio)gold is obtained.

Similarly, when an equivalent amount of triphenylphosphinegold( I)chloride is substituted in the proce dure of Example3 fortriethylphosphinegold(l) chloride,S-triphenylphosphine(2-aminophenylthio)gold is obtained.

EXAMPLE l0 S-Triethylphosphine( 2-aminothiobenzoyl.)gold When anequivalent amount of thioanthranilic acid (US. Pat. No. 3,123,631) issubstituted in the procedure of Example 1 for thiobenzoic acid, thetitle com pound is obtained EXAMPLE 1 1 EXAMPLE l2 S-Triethylphosphine(2-carboxythiobenzoyl gold Substitution of an equivalent amount ofmonothiophthalic acid [1. Indian Chem. 500., 5:397 (1928)] in theprocedure of Example 2 for o-mercaptobe'nzoic acid gives the titlecompound.

EXAMPLE 13 When monothiophthalicacid and triisopropylphosphinegold(l)chloride are substituted in the procedure of Example 2 for o-rnercaptobenzoic acid and triethylphosphinegoldfl) chloride,S-triisopropylphosphine(2 -carboxythiobenzoyl)gold is obtained.

In a similar manner, S-trimethylphosphine( 2- carboxythiobenzoyl)gold isprepared from monothiophthalic acid and trimethylphosphinegold(I)chloride.

Likewise, when monothiophthalic acid and triphenylphosphinegoldfl)chloride are used as starting materials, S-triphenylphosphine(2-carboxythiobenzoyl gold is obtained.

EXAMPLE 14 By following procedures outlined in J. Chem. $00.,

1828 (1937) trialkylphosphinegold(l) iodidezcomplexes are prepared, forexample, phinegold(l) iodide.

When an equivalent amount of triethylphosphinegold(l) iodide issubstituted in the procedure of Example 1 for triethylphosphinegoldfl)chloride, S- triethylphosphine(thiobenzoyl)gold is obtained.

Similarly, by following procedures outlined in J. Chem. Soc, 1235(1940), trialkylphosphinegold(l) bromide complexes are prepared, forexample, triethylphosphinegoldfl) bromide.

Substitution of an equivalent amount of triethylphosphinegold( I)bromide in the procedure of Example 1 for triethylphosphinegoldfl)chloride also gives S- triethylphosphine(thiobenzoyl)gold.

By similar procedures, the other phosphine gold complexes of Formula Imay be prepared as described from the appropriate phosphine gold(l)iodidesand bromides.

triethylphos- EXAMPLE l5 S-Triethylphosphite( thiobenzoyl gold Gold acidchloride trihydrate (5.9 g., 0.0l5' mol.) is reduced to aurous chloridewith 3.7 g. (0.03 mol.) of thiodigylcol in 1:2 aqueous ethanol. Thesolution is cooled to -l0 and an equally cold solution of 3.72 g. (0.02mol.) of triethylphosphite in 20 ml. of ethanol is added dropwise withstirring. The temperature is maintained at l0 and stirring is continuedfor 30 minutes. The ethanol is removed from the reaction mixture underreduced pressure without heating. The aqueous residue is extracted withmethylene chloride and the dried extract is evaporated in vacuo. Thecrude product is purified by chromatography on a silica column to givetriethylphosphitegoldfl) chloride as an oil.

When an equivalent amount of triethylphosphitegold(l) chloride issubstituted in the procedure of Example 1 for triethylphosphinegoldfl)chloride, the title compound is obtained.

EXAMPLE l6 S-Triethylphosphite( 2-carboxyphenylthio gold is prepared bysubstitution of an equivalent amount of triethylphosphitegoldfl)chloride in the procedure of Example 2 for triethylphosphinegoldfl)chloride.

Similarly, S-triethylphosphite(2-aminophenylthio)- gold is obtained fromsubstitution of an equivalent amount of triethylphosphitegoldfl)chloride in the procedure of Example 3 for: triethylphosphinegoldfl)chloride.

When an equivalent amount of triethylphosphitegoldfl) chloride issubstituted in the procedure of Example 10 for triethylphosphinegoldfl)chloride, S- triethylphosphite(2-aminothiobenzoyl)gold is obtained.

In like manner, substitution of an equivalent amount oftriethylphosphitegoldfl) chloride in the procedure of Example 12 fortriethylphosphinegold(l) chloride gives S-triethylphosphite( 2 -carboxythiobenzoyl gold EXAMPLE l7 S-Trimethylphosphite(thiobenzoyl )goldGold acid chloride trihydrate (4.0 g.) was reduced to aurous chloridewith 2.44 g. of thiodiglycol in 1:2 aqueous methanol. The resultingsolution was cooled to below and an equally cold solution of 1.5 g. oftrimethylphosphite in ml. of methanol was added dropwise with stirringunder nitrogen. The reaction mixture was stirred for 30 minutes,filtered and the solid was washed with cold aqueous methanol and dried.The product was dissolved in 5 ml. of chloroform, diluted with 10 ml. ofmethanol and filtered through charcoal. The filtrate was concentrated invacuo, cooled and diluted with ice-water to precipitatetrimethylphosphitegold(I) chloride, m.p. 99100.

Substitution of an equivalent amount of trimethylphosphitegold(I)chloride in the procedure of Example 1 for triethylphosphinegoldfl)chloride gives the title compound.

EXAMPLE 1 8 When an equivalent amount of trimethylphosphitegold(I)chloride is substituted in the procedures of Examples 2, 3, l0 and 12for triethylphosphinegoldfl) chloride, the following phosphite goldcomplexes are obtained, respectively:

S-trimethylphosphite( 2-carboxyphenylthio gold S-trimethylphosphite(2-aminophenylthio gold S-trimethylphosphite( 2-aminothiobenzoyl goldS-trimethylphosphite( 2-carboxythiobenzoyl gold.

' EXAMPLE l9 S-Triphenylphosphite(thiobenzoyl)gold When an equivalentamount of triphenylphosphite is substituted in the procedure of Examplefor triethylphosphite, triphenylphosphitegold(l) chloride is obtained.

Substitution of an equivalent amount of triphenylphosphitegold(l)chloride in the procedure of Example 1 for triethylphosphinegoldfl)chloride gives the title compound.

EXAMPLE When an equivalent amount of triphenylphosphitegold (l) chlorideis substituted in the procedures of Example 2, 3, l0 and 12 fortriethylphosphinegold(l) chloride, the following phosphite goldcomplexes are obtained, respectively:

- Y s S-triphenylphosphite( 2-carboxyphenylthio)goldS-triphenylphosphite( 2-aminophenylthio)gold S-triphenylphosphite(2-aminothiobenzoyl )gold S-triphenylphosphite(Z-carboxythiobenzoyl)gold.

EXAMPLE)! 1; Ingredients MgJTabIet S-Trlethylphosphlne(Z-cnrboxy- 5phenylthio)gold Calcium sulfate, dihydrate 150 Sucrose 25 Starch I I5Talc 5 Stearic acid 3 The sucrose, calcium sulfate and S-triethylphosphine(2-carboxyphenylthio)gold are thoroughly mixed andgranulated with hot 10% gelatin solution. The wetted mass is passedthrough a No. 6. mesh screen directly onto drying trays. The granulesare dried at F. and passed through a No. 20 mesh screen, mixed with thestarch, talc and stearic acid and compressed into tablets.

I In a similar manner, the other phosphine or phosphite gold complexesdisclosed herein may be formulated into tablets.

What is claimed is:

l. A pharmaceutical composition having antiarthritic activity, in dosageunit form, comprising a pharmaceutical carrier and an effective butnontoxic amount of a compound of the formula:

in which:

R is lower alkyl, lower alkoxy, phenyl or phenoxy with each alkyl oralkoxy having from one to three carbon atoms;

Y is a carbon-sulfur single bond or C=O;

R is hydrogen, amino or COOM when Y is C=O, or amino or COOM when Y is acarbon-sulfur single bond; and

M is hydrogen or an anti-arthritically alkali metal cation.

2. The composition of claim 1 in which R is lower alkyl of from one tothree carbon atoms.

3. The composition of claim 2 in which R is hydrogen and Y is C=O.

4. The composition of claim 3 in which R is ethyl.

5. The composition of claim 2 in which R is carboxy and Y is acarbon-sulfur single bond.

6. The composition of claim 5 in which R is ethyl.

7. The composition of claim 2 in which R is amino and Y is acarbon-sulfur single bond.

8. The composition of claim 7 in which R is ethyl.

9. The composition of claim 1 in which the active medicament is in anamount of about 0.5 mg. to about 5 mg. per dosage unit, calculated ongold content.

10. The method of producing anti-arthritic activity which comprisesadministering internally to an animal organism in need of said activityin an amount suffii and Y is a carbon-sulfur single bond.

9 l cient to produce said activity a compound as defined in 14; Themethod of claim 11 in which R is amino and claim I. Y is a carbon-sulfursingle bond.

l l. The method of claim in which R is lower alkyl The method of claim10 in which the active medi of from one to three carbon atoms cament isadministered in a dail dosa e re imen of 12. The method of claim 11 inwhich R is hydrogen 5 y g g and Y is about 0.5 mg. to about 5 mg.,calculated on gold con- 13. The method of claim 11 in which R is carboxyi l l ill l UNITED sTATEs EATEET AND TRADEMARK eEETEE QETFTQA'T EQTSeptember 2, 1975 INVENTOR(S) Blaine M'a Sutton and Joseph WeinstockPATENT NO.

DATED It is certified that error appears in the above-identified patentand that said Letters Patent are hereby corrected as shown below:

Column 1, Formula I should appear as:

Column 2, line 35 'r/rhere' should read -when-- Column 2, line 41 delete"pextin" insert acacia, after "pectin,"

Column 5, line 10 "-(Z-carboxyphenylethio)gold" should read-(Z-carboxyphenylthio)gold Column 8, Claim 1, line 30 after "an" insertanti-arthritically line 49 delete "anti-arthritically" en's igm

Third of August 1976 [SEAL] Attest:

C. MARSHALL DANN Commissioner ufPatents and Trademarks RUTH C. MASONArresting Officer

1. A PHARAMACEUTICAL CMPOSITION HAVING ANTI-ARTHITIC ACTIVITY, IN DOSAGE UNIT FORM, COMPRISING A PHARMACEUTICAL CARRIER AND AN EFFECTIVE BUT NONTOXIC AMOUNT OF A COMPOUND OF THE FORMULA:
 2. The composition of claim 1 in which R1 is lower alkyl of from one to three carbon atoms.
 3. The composition of claim 2 in which R2 is hydrogen and Y is C O.
 4. The composition of claim 3 in which R1 is ethyl.
 5. The composition of claim 2 in which R2 is carboxy and Y is a carbon-sulfur single bond.
 6. The composition of claim 5 in which R1 is ethyl.
 7. The composition of claim 2 in which R2 is amino and Y is a carbon-sulfur single bond.
 8. The composition of claim 7 in which R1 is ethyl.
 9. The composition of claim 1 in which the active medicament is in an amount of about 0.5 mg. to about 5 mg. per dosage unit, calculated on gold content.
 10. The method of producing anti-arthritic activity which comprises administering internally to an animal organism in need of said activity in an amount sufficient to produce said activity a compound as defined in claim
 1. 11. The method of claim 10 in which R1 is lower alkyl of from one to three carbon atoms.
 12. The method of claim 11 in which R2 is hydrogen and Y is C O.
 13. The method of claim 11 in which R2 is carboxy and Y is a carbon-sulfur single bond.
 14. The method of claim 11 in which R2 is amino and Y is a carbon-sulfur single bond.
 15. The method of claim 10 in which the active medicament is administered in a daily dosage regimen of about 0.5 mg. to about 5 mg., calculated on gold content. 